Minimally invasive biomarkers for triaging lung nodules—challenges and future perspectives

Abstract CT chest scans are commonly performed worldwide, either in routine clinical practice for a wide range of indications or as part of lung cancer screening programs. Many of these scans detect lung nodules, which are small, rounded opacities measuring 8–30 mm. While the concern about nodules is that they may represent early lung cancer, in screening programs, only 1% of such nodules turn out to be cancer. This leads to a series of complex decisions and, at times, unnecessary biopsies for nodules that are ultimately determined to be benign. Additionally, patients may be anxious about the status of detected lung nodules. The high rate of false positive lung nodule detections has driven advancements in biomarker-based research aimed at triaging lung nodules (benign versus malignant) to identify truly malignant nodules better. Biomarkers found in biofluids and breath hold promise owing to their minimally invasive sampling methods, ease of use, and cost-effectiveness. Although several biomarkers have demonstrated clinical utility, their sensitivity and specificity are still relatively low. Combining multiple biomarkers could enhance the characterisation of small pulmonary nodules by addressing the limitations of individual biomarkers. This approach may help reduce unnecessary invasive procedures and accelerate diagnosis in the future. This review offers a thorough overview of emerging minimally invasive biomarkers for triaging lung nodules, emphasising key challenges and proposing potential solutions for biomarker-based nodule differentiation. It focuses on diagnosis rather than screening, analysing research published primarily in the past five years with some exceptions. The incorporation of biomarkers into clinical practice will facilitate the early detection of malignant nodules, leading to timely interventions and improved outcomes. Further efforts are needed to increase the cost-effectiveness and practicality of many of these applications in clinical settings. However, the range of technologies is advancing rapidly, and they may soon be implemented in clinics in the near future. Graphical abstract